Proteolytic cleavages of the amyloid precursor protein (APP) generate beta-amyloid peptides (A?). Although beta-amyloid pathology is the hallmark of Alzheimer's disease (AD), synaptic dysfunction is believed to play a primary role in AD pathogenesis. Since A? is produced as part of APP processing, we reasoned that understanding the mechanisms of APP and its processing products in synaptic function, and investigating the effects of A? in the context of APP are of crucial importance. Whereas various neuronal and synaptic activities of APP have been proposed, their physiological relevance remains largely unestablished. To this end, we generated mice deficient in APP and reported that APP plays a functional role in hippocampal synaptic plasticity and learning and memory. We recently created a strain of APP conditional knockout mice. Analysis of these animals demonstrates an essential role for the APP family of proteins in neuronal survival and synaptic structure and function. Intriguingly, APP-mediated synaptogenic activity requires its expression in both pre- and postsynaptic compartments, supporting a functional interaction of APP across synapse. Our proposal is aimed at testing this trans-synaptic APP interaction model, deciphering the activities of APP processing products, including A?, in APP-mediated synaptic property, and identifying the APP downstream targets using a combination of state-of-the-art in vitro technologies and physiological and disease-relevant mouse models. In particular, we are equipped with the novel APP conditional knockout mice and humanized APP/A? knock-in mice and are uniquely positioned to address these fundamental questions concerning the pathophysiology of APP and A? in central synapses.

Public Health Relevance

APP plays a central role in AD pathogenesis;synaptic dysfunction is widely accepted as the primary cause of AD. Although A? has been the focus of AD research, it is often overlooked that it is generated as part of normal APP processing. As such, physiology is intimately linked with pathogenesis, and deregulation of A? is expected to simultaneously affect other APP metabolites and APP-mediated pathways. Our recent finding that APP may function as a synaptic adhesion protein and that APP family of proteins is essential for the maintenance of adult neurons open up a new and exciting direction for achieving a fundamental understanding of the pathophysiology of APP. Accordingly, determining the molecular and cellular mechanisms of APP in neuronal and synaptic regulation and investigating the effect of A? in the context of APP using physiological and disease relevant mouse model systems as proposed represent a novel and much needed area of AD research. Our studies will provide a comprehensive understanding of the role of APP in synaptic regulation and reveal new pathogenic insights into Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Refolo, Lorenzo
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Baylor College of Medicine
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Lian, Hong; Yang, Li; Cole, Allysa et al. (2015) NF?B-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease. Neuron 85:101-115
Wang, Baiping; Wang, Zilai; Sun, Lu et al. (2014) The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons. J Neurosci 34:13314-25
Wiese, Mary; Antebi, Adam; Zheng, Hui (2012) Regulation of neuronal APL-1 expression by cholesterol starvation. PLoS One 7:e32038
Müller, Ulrike C; Zheng, Hui (2012) Physiological functions of APP family proteins. Cold Spring Harb Perspect Med 2:a006288
Guo, Qinxi; Li, Hongmei; Gaddam, Samson S K et al. (2012) Amyloid precursor protein revisited: neuron-specific expression and highly stable nature of soluble derivatives. J Biol Chem 287:2437-45
Wang, Zilai; Yang, Li; Zheng, Hui (2012) Role of APP and Aýý in synaptic physiology. Curr Alzheimer Res 9:217-26
Guo, Qinxi; Wang, Zilai; Li, Hongmei et al. (2012) APP physiological and pathophysiological functions: insights from animal models. Cell Res 22:78-89
Shim, David J; Yang, Li; Reed, J Graham et al. (2011) Disruption of the NF-?B/I?B? Autoinhibitory Loop Improves Cognitive Performance and Promotes Hyperexcitability of Hippocampal Neurons. Mol Neurodegener 6:42
Li, Hongmei; Wang, Baiping; Wang, Zilai et al. (2010) Soluble amyloid precursor protein (APP) regulates transthyretin and Klotho gene expression without rescuing the essential function of APP. Proc Natl Acad Sci U S A 107:17362-7
Hernandez, Caterina M; Kayed, Rakez; Zheng, Hui et al. (2010) Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease. J Neurosci 30:2442-53

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